A stereodivergent approach to amino acids, amino alcohols, or oxazolidinones of high enantiomeric purity

Article abstract of DOI:10.1021/ol048936q

(-)-Menthone, an inexpensive chiral auxiliary, was used to prepare both enantiomers of α-amino acids, amino alcohols, or oxazolidinones. The sequence includes the S_N2′ displacement by a cuprate reagent and a Curtius rearrangement as key steps.

Full text of DOI:10.1021/ol048936q

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2801-2804
A Stereodivergent Approach to Amino
Acids, Amino Alcohols, or
Oxazolidinones of High Enantiomeric
Purity
Claude Spino,* Marie-Claude Tremblay, and Ce´drickx Gobdout
De´partement de Chimie, UniVersite´ de Sherbrooke, 2500 Boul. UniVersite´,
Sherbrooke, QC, Canada J1K 2R1
claude.spino@usherbrooke.ca
Received June 7, 2004
ABSTRACT
(−)-Menthone, an inexpensive chiral auxiliary, was used to prepare both enantiomers of r-amino acids, amino alcohols, or oxazolidinones.
The sequence includes the SN2′ displacement by a cuprate reagent and a Curtius rearrangement as key steps.
Amino acids1 and amino alcohols2,3 are compounds of im-
mense interest and importance for the pharmaceutical in-
Scheme 1. Strategy for Making Chiral Carbonyl Compounds
dustry. In addition to their medicinal importance, they are
widely being used as chiral ligands for many organic trans-
formations.2,3 Herein, we report a stereodivergent and ef-
ficient route to prepare amino alcohols of high enantiomeric
purity.4 The latter can be converted to amino acids or oxa-
zolidinones, of course, but our strategy also allows for the
direct preparation of amino acids or oxazolidinones without
the intermediacy of amino alcohols. In addition, amino
aldehydes can be prepared.
We have reported earlier the sequence shown in Scheme
1 to create chiral centers R to a carbonyl with optical purities
>99%.5 In this strategy, menthone serves as a readily
(1) (a) For a review on synthetic methods of R-amino acids, see:
available and recyclable chiral auxiliary for a short sequence
of reactions that includes as one of the key steps the highly
Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (b) Williams, R. H.
Synthesis of Optically ActiVe R-Amino Acids; Pergamon Press: New York,
1989. (c) Schollkopf, U. Top. Curr. Chem. 1983, 109, 65-84.
(2) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(3) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30,
3-12.
(5) (a) Spino, C.; Beaulieu, C.; Lafrenie`re, J. J. Org. Chem. 2000, 65,
7091-7097. (b) Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998, 120,
11832-11833. (c) Spino, C.; Beaulieu, C. Tetrahedron Lett. 1999, 40,
1637-1640.
(4) R,R-Dialkylated amino acids can be made from a related system.
See: Spino, C.; Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106-12107.
10.1021/ol048936q CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/08/2004

regioselective and stereospecific SN2′ displacement of an
allylic carbonate by a cuprate reagent.6,7 This alternative to
chiral enolate alkylation is very broad in scope and allows
the synthesis of hindered chiral carbons next to a carbonyl.8
We envisaged that if compound 2 contained a hydroxy-
methyl substituent (R1 ) CH2OH), we could access very
easily chiral amines 8 using the Curtius rearrangement or
its analogues (Scheme 2, eq 1).9 Compound 8 would be easily
Scheme 3. Synthesis of Alkenes 7
Scheme 2. Stereodivergent Synthetic Design of Amino Acids
drozirconation protocol10 (Scheme 3). Iodine-lithium ex-
change and addition of the resulting vinyllithium to menthone
in the presence of dry CeCl3 afforded high yields of alcohols
13a,b, each as a single diastereomer. Conversion of each
alcohol to the carbonate followed by addition of a dialkyl
or cyanoalkyl cuprate gave a series of diastereomerically pure
alkenes 7a-c (GC analysis). For unknown reasons, com-
pound 7d was only 88% de, even though we have added
cyclohexylcuprates to a similar system before and obtained
the usual >99% de.11
The sequence shown above is efficient because a single
alcohol 13 may serve to prepare a whole series of alkenes 7
via the carbonate-cuprate sequence. This would be particu-
larly advantageous in the context of making combinatorial
libraries of amino acids or derivatives.12 However, some
cuprate reagents are difficult to prepare, are unreactive, or
may add with a lower stereospecificity. For example, the
cuprate reagents derived from cyclohexylmagnesium bromide
added with only 88% de to 13b. In such cases, the desired
compound can still be accessed as shown below. We pre-
pared alcohol 16 from the addition of lithium cyclohexyl-
acetylide (derived from cyclohexylcarboxaldehyde 14 via the
Corey-Fuchs procedure) to menthone 1 (Scheme 4).13 Com-
pound 15 was isolated as a 7:1 mixture of two alcohols easily
separable by silica gel column chromatography. The alkyne
in 15 was then reduced to the E-alkene 16 with Red-Al.
Alternatively, the cyclohexylacetylene could be isolated,
converted to the corresponding vinyliodide and then to the
vinyllithium, and added to 1 with complete stereoselectivity,
thus alleviating the need for diastereomer separation. Adding
the cuprate derived from the lithium anion of tert-butylmethyl
ether to the carbonate made from 16 furnished adduct 7e
with complete transfer of chirality.
converted to the amino acid 9 by ozonolysis under oxidative
workup. Likewise, amino alcohols would be accessible by a
simple change in the treatment of the ozonide, whereas
oxazolidinones would be obtained by heating the intermediate
hydroxy-carbamate or isocyanate with base. Importantly, we
realized that this system could be used to make both
enantiomers of an amino acid from a single precursor 7
simply by inverting the sequence of reactions (Scheme 2,
eq 2). Thus, oxidative cleavage of the auxiliary would permit
the Curtius rearrangement, and oxidation of the primary
alcohol would complete the desired synthesis. Added to the
fact that menthone is available in both enantiomeric series
and that R1 and R2 are interchangeable (vide infra), this
method looked very flexible indeed.
This prediction was born out. We prepared vinyliodides
12a and 12b from the cheaply available propargyl alcohol
using standard O-silylation techniques and Schwartz’s hy-
(6) (a) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.;
Knochel, P. Org. Lett. 2003, 5, 2111-2114. (b) Belelie, J. L.; Chong, J.
M. J. Org. Chem. 2001, 66, 5552-5555. (c) Belelie, J. L.; Chong, J. M. J.
Org. Chem. 2002, 67, 3000-3006. (d) Denmark, S. E.; Marble, L. K. J.
Org. Chem. 1990, 55, 1984-1986.
(7) For other related approaches, see: (a) Kakinuma, K.; Li, H.-Y.
Tetrahedron Lett. 1989, 30, 4157-4160. (b) Kakinuma, K.; Koudate, T.;
Li, H.-Y.; Eguchi, T. Tetrahedron Lett. 1991, 32, 5801-5804. (c) Eguchi,
T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527-4540. (d)
Clayden, J.; McCarthy, C.; Cumming, J. G. Tetrahedron Lett. 2000, 41,
3279-3283. (e) Savage, I.; Thomas, E. J.; Wilson, P. D. J. Chem. Soc.,
Perkin Trans. 1 1999, 3291-3303. (f) Clayden, J.; McCarthy, C.; Cumming,
J. G. Tetrahedron: Asymmetry 1998, 9, 1427-1440. (g) Hung, S.-C.; Wen,
Y. F.; Chang, J.-W.; Liao, C.-C.; Uang, B. J. J. Org. Chem. 2002, 67, 1308-
1313.
There is no particular advantage to using the sequence
depicted in Scheme 4, because a different alcohol (16) must
(8) For a review on chiral enolate equivalent, see: Spino, C. Org. Prep.
Proced. Int. 2003, 35, 1-140.
(9) For selected examples of the use of Curtius or similar rearrangements
in making amino acids, see: (a) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.;
Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64,
6411-6417. (b) Braibante, M. E. F.; Braibante, H. S.; Costenaro, E. R.
Synthesis 1999, 943-947. (c) Ghosh. A. K.; Fidanze, S. J. Org. Chem.
1998, 63, 6146-6152. (d) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem.
1997, 62, 5864-5872. (e) Charette, A. B.; Coˆte´, B. J. Am. Chem. Soc.
1995, 117, 12721-12732. (f) Tanaka, M.; Oba, M.; Tamai, K.; Suemune,
H. J. Org. Chem. 2001, 66, 2667-2673.
(10) (a) Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett.
1990, 31, 7257-7260. (b) Schwartz, J.; Labinger, J. A. Angew. Chem., Int.
Ed. Engl. 1976, 15, 333-340.
(11) See ref 5. The source of the cyclohexylmagnesium bromide or
chloride was varied without success in this particular case.
(12) We have developed a resin-bound version of this chiral auxiliary.
Patent 2,413,713 filed for Canada-U.S. in December 2003. Manuscript for
publication in preparation.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-3772.
2802
Org. Lett., Vol. 6, No. 16, 2004

Then, we converted adducts 7a-d to the corresponding
amido alcohols 17a-d via the carbamate 8 (Scheme 6, Table
Scheme 4. Synthesis of Alkene 7e
Scheme 6. Synthesis of Amino Alcohols (R)-17a-d, Amino
Acids (R)-9b,c, and Oxazolidinones (R)-18b,c
be prepared for each desired amino acid. However, it is
stereochemically complementary to the sequence depicted
in Scheme 3, and in addition, it may provide alkene 7 with
increased enantiomeric excess, as was the case for 7e vs 7d.
We first tested the Curtius rearrangement on 7a. The
primary alcohol was deprotected and oxidized in the same
step while the resulting carboxylic acid was treated with
diphenylphosphoryl azide in toluene at reflux to give, after
heating the intermediate isocyanate at reflux in methanol,
carbamate 8a (Scheme 5). Carbamates 8f and 8g were
1, entries 5-8). The cyclization to the oxazolidinone
18a-d15 was performed with potassium carbonate in reflux-
Table 1. Preparation of Amino-acids 9, Alcohols 17, and
Oxazolidinones 18
entry
product
R2
yield (%)
% ee
1
2
3
4
5
6
7
8
(R)-9b
(R)-9c
(S)-9b
(S)-9d
1-naphth
2-naphth
1-naphth
c-C6H11
t-Bu
1-naphth
2-naphth
c-C6H11
1-naphth
c-C6H11
t-Bu
1-naphth
2-naphth
c-C6H11
1-naphth
c-C6H11
64
81
72
84
81
76
58
65
93
81
73
82
80
96
82
78
>99
>99
>99
>99
>99a
>99b
>99b
90a,c
>99b
>99a
>99
>99d
>99d
90c
Scheme 5. Synthesis of Carbamates 8a,f,g from 7a
(R)-17a
(R)-17b
(R)-17c
(R)-17d
(S)-17b
(S)-17d
(R)-18a
(R)-18b
(R)-18c
(R)-18d
(S)-18b
(S)-18d
9
10
11
12
13
14
15
16
>99
>99e
a Determined by 19F NMR of the corresponding Mosher esters. b De-
termined by HPLC of the corresponding oxazolidinone. c Prepared from
7d, which was 90% de. d Determined by HPLC. e Prepared from 7e.
prepared by trapping the isocyanate intermediate with tert-
butyl alcohol or 9-fluorenylmethanol, respectively. Note that
we chose to make the methyl carbamate in all of the other
cases because it facilitates the cyclization to the oxazolidi-
none subsequently. Compound 8g was amenable to single-
crystal X-ray diffraction analysis, which confirmed the
stereochemistry of 7a and, by inference, of all other cuprate
adducts. The carbamate 8g was then transformed to N-
protected tert-leucine 9g by ozonolysis to the aldehyde and
subsequent oxidation with NaClO2. The mildness of these
conditions to generate the highly sensitive amido aldehydes
is noteworthy. Such molecules are sensitive but useful
intermediates for the synthesis of complex amino alcohols
and alkaloids.14
ing methanol (entries 11-14). The amino acids 9b,c were
made by Jones oxidation of the alcohols 7b,c (entries 1 and
2).16 The % ee of each amino alcohol 17 was determined by
fluorine NMR of the corresponding Mosher ester or by chiral
HPLC on the corresponding oxazolidinone.
(15) 18a: Dauz, K.; Jahn, W.; Schwarm, M. Chem. Eur. J. 1995, 1,
538-540. 18b: Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1983, 48,
2520-2527. 18c: Takacs, J. M.; Jaber, M. R.; Vellekoop, A. S. J. Org.
Chem. 1998, 63, 2742-2748. 18d: Evans, D. A.; Chapman, K. T.; Bisaha
J. J. Am. Chem. Soc. 1988, 110, 1238-1256.
(16) This method of oxidation has been shown to proceed without
racemization of the amino acid. See: (a) Kashima, C.; Harada, K.; Fujioka,
Y.; Maruyama, T.; Omote, Y. J. Chem. Soc., Perkin Trans. 1 1988, 535-
539. (b) Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem. 2002, 67,
4475-4486.
(14) See, for example: Gryko, D.; Chalko, J.; Jurczak, J. Chirality 2003,
15, 514-541.
Org. Lett., Vol. 6, No. 16, 2004
2803

divergence strategy is not needed, the reason being that it
can be cleaved in the oxidation step with the Jones reagent
(i.e., the TBAF step becomes unnecessary).
A shorter route to oxazolidinone is also possible. When
7e was ozonolyzed to the acid and the alcohol deprotected,
this free alcohol cyclized the moment the intermediate iso-
cyanate was formed after the Curtius rearrangement (Scheme
8). This is actually the method of choice to make oxazoli-
Scheme 7. Synthesis of Amino Acid (S)-9b, Amino Alcohol
(S)-17b, and Oxazolidinone (S)-18b via a Stereodivergent
Approach
Scheme 8. Cyclization to Oxazolidinone 18e Immediately
after Curtius Rearrangement
In the case of 7e, the t-Bu protecting group was removed
using FeCl3/acetic acid followed by hydrolysis to give the
free primary alcohol in 96% yield.17 This alcohol led to (S)-
17d and thus to (S)-18d (entries 10 and 16) using the same
reaction sequence as per (R)-17d, except the enantiomeric
excess was now >99%.
We then tackled the question of stereodivergence in the
strategy. We succeeded in making both enantiomers of each
of the amino acid 9b, amino alcohol 17b, and oxazolidinone
18b starting from a single intermediate 7b (Scheme 6, R2 )
1-naphth). The S isomer of these compounds was prepared
by reversing the order of reactions used for the R isomer.
Ozonolysis of 7b to the carboxylic acid followed by a Curtius
rearrangement yielded carbamate 10b (Scheme 7). Depro-
tection of the primary alcohol afforded (S)-17b (entry 9),
which was converted to the amino acid (S)-9b (entry 3) and
oxazolidinone (S)-18b (entry 15).
dinones if the corresponding amino acids or amino alcohols
are not needed.
In conclusion, we have developed an efficient methodol-
ogy to prepare amino acids and related molecules in high
optical purity. Extensions of this strategy to other chiral
compounds are underway in our laboratory.
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada, Boehringer-Ingelheim
(Canada) Ltd., The ACS Petroleum Research Fund (Grant
No. 36256-AC1), and the Universite´ de Sherbrooke for
financial support.
Supporting Information Available: Experimental and
NMR spectra for all new compounds and ORTEP drawing
of 8g. This material is available free of charge via the Internet
at http://pubs.acs.org.
The tert-butyldimethylsilyl protecting group in 7 is more
appropriate than its tert-butyldiphenyl analogue if the
(17) Alexakis, A.; Gardette, M.; Colin, S. Tetrahedron Lett. 1988, 29,
2951-2954.
OL048936Q
2804
Org. Lett., Vol. 6, No. 16, 2004